嵌合抗原受体
癌症研究
免疫疗法
医学
胰腺癌
免疫系统
抗原
肿瘤微环境
癌症
免疫学
内科学
作者
A. Barrett,Zachary T. Britton,Rosa Carrasco,Shannon Breen,Maria A. S. Broggi,A.L. Hatke,Benjamin Clark,Chunning Yang,Sandrina Phipps,Lorenzo Burgos Ortiz,Brianna L. Janocha,Peter Zanvit,Nicolás A. Giraldo,Philip L. Martin,Jean−Martin Lapointe,Nathalie Harder,Georgina H. Cornish,Bala Attili,Yariv Mazor,Melissa Damschroder,Mark Cobbold,Gordon Moody,Emily E. Bosco
标识
DOI:10.1158/1078-0432.ccr-24-1853
摘要
Abstract Purpose: CLDN18.2 is a surface membrane protein crucial for maintaining tight junctions in gastric mucosal cells and is highly expressed in gastric, esophageal, and pancreatic cancers. Thus, CLDN18.2 is suited for exploration as a clinical target for chimeric antigen receptor T-cell (CAR-T) therapy in these indications. Although CAR-T therapies show promise, a challenge faced in their development for solid tumors is the immunosuppressive tumor microenvironment, often characterized by the presence of immune and stromal cells secreting high levels of transforming growth factor beta (TGF-β). Addition of TGF-β armoring can potentially expand CAR-T activity in solid tumors. We report on the preclinical development of a CLDN18.2-targeting CAR-T showing effectiveness in CLDN18.2-positive gastric, esophageal, and pancreatic tumor models. Experimental Design: The lead lentivirus product contains a unique single-chain variable fragment, CD28 and CD3z costimulatory and signaling domains, and dominant negative TGF-β receptor armoring, enhancing targeting and safety and counteracting suppression. We developed a shortened cell manufacturing process to enhance the potency of the final product, AZD6422. Results: AZD6422 exhibited significant antitumor activity and tolerability in multiple patient-derived tumor xenograft models with various CLDN18.2 and TGF-β levels, as determined by immunohistochemistry. Efficacy of armored CAR-Ts in tumor models with elevated TGF-β was increased in vitro and in vivo. In vitro restimulation assays established greater persistence and cytolytic function of AZD6422 compared with a traditionally manufactured CAR-T. Conclusions: AZD6422 was safe and efficacious in patient-derived, CLDN18.2-positive murine models of gastrointestinal cancers. Our data support further clinical development of AZD6422 for patients with these cancers.
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